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Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing1-8. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.
A common denominator of numerous pathological conditions and ageing is a deregulation of cellular mitochondrial content1-8. To uncover the cellular and molecular underpinnings of mitochondrial mass homeostasis, we examined the involvement of mitochondriaselective autophagy (mitophagy) in regulating mitochondrial content of C. elegans during ageing. Mitochondria gradually accrue with age in wild-type nematodes1 (Fig. 1a and Extended Data Fig. 1a-d). Depletion of the Atg6/Vps30/Beclin1 homologue BEC-1, the main autophagy regulator in worms9, recapitulates the effect of ageing on mitochondrial mass in young adult animals (Fig. 1b). Thus, failure of autophagy impairs the removal ofmitochondria and may contribute to progressive accumulation of mitochondria during ageing.
To target mitophagy specifically, we knocked down dct-1 (DAF-16/ FOXOControlled, germlineTumour affecting-1)10,11, a putative orthologue to the mammalian NIX/BNIP3L and BNIP3 (Nip3-like protein X/Bcl-2 and adenovirus E1B interacting protein; Extended Data Fig. 2a), which act as mitophagy receptors in mammals12-15. DCT-1 is widely expressed throughout development as an integral membrane protein and localized on the outer mitochondrial membrane (Extended Data Fig. 2b-g). Expression of dct-1 is partly controlled by the FOXO transcription factor DAF-16 and is elevated upon low insulin/IGF-1 signalling10,11 (Extended Data Fig. 1e, f). Similarly to BEC-1, DCT-1 deficiency increases intestinal and muscle cell mitochondrial content in young adult animals and distorts mitochondrial network morphology (Fig. 1c, d and Extended Data Figs 1g-k and 3a-c). DCT-1 encompasses a WXXL motif...